Journal
CELL
Volume 171, Issue 1, Pages 163-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.07.036
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Funding
- Department of Defense Prostate Cancer Research Program Postdoctoral Training Award [W81XWH-15-1-0659]
- Swiss National Science Foundation [PP00P3-157468/1]
- MEDIC Foundation
- NIH Pathway to Independence Award [1K99CA212154]
- NIH DP2 New Innovator Award [1DP2CA195762-01]
- American Cancer Society Research Scholar Award [RSG-14-051-01-DMC]
- Pew-Stewart Scholars in Cancer Research Grant
- Alex's Lemonade Stand Foundation Young Investigator Award
- V Foundation for Cancer Research
- Affymetrix
- Swiss National Science Foundation (SNF) [PP00P3_157468] Funding Source: Swiss National Science Foundation (SNF)
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Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.
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